Biologically motivated computational modeling of formaldehyde carcinogenicity in the F344 rat
Biologically motivated computational modeling of formaldehyde carcinogenicity in the F344 rat
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DOI：
10.1093/toxsci/kfg182
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发表时间：
2003-10-01
影响因子：
3.8
通讯作者：
Miller, FJ
中科院分区：
文献类型：
--
作者：
Conolly, RB;Kimbell, JS;Miller, FJ
吸入6ppm及以上的甲醛可引起F344大鼠的鼻鳞状细胞癌。这种效应对人类健康的影响是非常重要的，因为人类广泛暴露于环境甲醛中，尽管浓度低于导致大鼠癌症的浓度。在这篇文章中，这是一个更大的努力，以预测人类吸入甲醛的癌症风险的一部分，我们描述了生物学动机的定量建模的肿瘤反应连续在大鼠。F344大鼠鼻气道的解剖学上现实的三维流体动力学模型用于预测甲醛从吸入空气进入组织的位点特异性通量，因为SCC和癌前病变都以特征性位点特异性模式发展。进入组织的通量被用作两种作用模式（直接致突变性和细胞致死性-再生细胞增殖（CRCP））的剂量度量，这反过来又与两阶段克隆生长模型的关键参数相关。直接致突变作用模式由DNA-蛋白质交联（DPX）形成的低剂量线性剂量反应模型表示。CRCP采用经验J型剂量反应模型和与经验数据拟合的阈值模型。在克隆生长模型中，每代细胞的突变概率是DPX的组织浓度的函数，而细胞分裂速率是根据CRCP数据计算的。使用最大似然法估计参数值。使用来自国家毒理学计划数据库和两项甲醛吸入生物测定的对照组存活率（非肿瘤结局）和肿瘤数据进行可能性计算。CRCP的J形剂量反应比阈值模型更好地描述了SCC数据。敏感性分析表明，啮齿动物肿瘤反应是由于CRCP的作用模式，直接致突变途径几乎没有影响（如果有的话）。当根据建模和数据库的不确定性进行评估时，特别是克隆生长模型的规范和CRCP的剂量反应数据，这项工作为甲醛介导的鼻SCC的J形剂量反应提供了暗示性但非决定性的证据F344大鼠。
Formaldehyde inhalation at 6 ppm and above causes nasal squamous cell carcinoma (SCC) in F344 rats. The human health implications of this effect are of significant interest since human exposure to environmental formaldehyde is widespread, though at lower concentrations than those that cause cancer in rats. In this article, which is part of a larger effort to predict the human cancer risks of inhaled formaldehyde, we describe biologically motivated quantitative modeling of the exposure-tumor response continuum in the rat. An anatomically realistic, three-dimensional fluid dynamics model of the F344 rat nasal airways was used to predict site-specific flux of formaldehyde from inhaled air into tissue, since both SCC and preneoplastic lesions develop in a characteristic site-specific pattern. Flux into tissue was used as a dose metric for two modes of action, direct mutagenicity and cytolethality-regenerative cellular proliferation (CRCP), which in turn were linked to key parameters of a two-stage clonal growth model. The direct mutagenicity mode of action was represented by a low dose linear dose-response model of DNA-protein cross-link (DPX) formation. An empirical J-shaped dose-response model and a threshold model fit to the empirical data were used for CRCP. In the clonal growth model, the probability of mutation per cell generation was a function of the tissue concentration of DPX while the rate of cell division was calculated from the CRCP data. Maximum likelihood methods were used to estimate parameter values. Survivor (a nontumor outcome) and tumor data for controls from the National Toxicology Program database and from two formaldehyde inhalation bioassays were used for likelihood calculations. The J-shaped dose-response for CRCP provided a better description of the SCC data than did the threshold model. Sensitivity analyses indicated that the rodent tumor response is due to the CRCP mode of action, with the directly mutagenic pathway having little, if any, influence. When evaluated in light of modeling and database uncertainties, particularly the specification of the clonal growth model and the dose-response data for CRCP, this work provides suggestive though not definitive evidence for a J-shaped dose-response for formaldehyde-mediated nasal SCC in the F344 rat.